Melanoma tumors metastasize at an early stage of development and are notoriously resistant to chemotherapeutics. We recently utilized a systems-level RNAi screening approach to uncover the molecular regulators of melanoma chemoresistance. These studies determined that RhoJ and its downstream kinase PAK1 suppress pathways in melanoma cells that sense DNA damage. Additional studies revealed that RhoJ and PAK1 also regulate melanoma invasion by modulating actin cytoskeletal dynamics. These observations led us to hypothesize that PAK kinases phosphorylate downstream targets that suppress DNA damage sensing and promote melanoma metastasis. In this proposal, we determine how PAK1 suppresses DNA damage sensing and determine whether Pak1 suppresses DNA damage sensing in vivo. Additional studies will identify PAK kinase targets that modulate melanoma cell invasion and verify that PAK kinases regulate melanoma metastasis in vivo. In the final aim of the proposal, we will examine whether PAK kinases are selectively activated in poor prognosis/chemoresistant human melanomas and determine whether PAK inhibitors can both sensitize mouse melanomas to chemotherapeutics and inhibit murine melanoma metastasis. Completion of these studies will lead to the design of more effective PAK inhibitors that can be used to treat metastatic melanoma.